Certain 3, 4-diaryl-delta2-1, 2, 5-thiadiazoline-1, 1-dioxides and their preparation



United States Patent C) CERTAHN 3,4-DlARYL-A -1,2,5-TH1ADHAZDLENE Ll-DIQXIDES AND THEIR PREPARATEUN John E. Wright, Kalamazoo Township, Kalamazoo County, Miclu, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed May 13, 1963, Ser. No. 280,114 9 Claims. (Cl. 2603l)l) This invention pertains to novel organic compounds and to a process for preparing the same. More particularly, the invention is directed to novel 3,4-disubstituted- A l,2,5-thiadiazo-line-1,1-dioxides, and to a process for prep-airing them.

The novel compounds of the invention can be represented by the following structural formula:

wherein X is selected from the group consisting of loweralkyl of from 1 to 4- carbon atoms, inclusive, lower-alkoxy of from 1 to 4 carbon atoms, inclusive, and halogen; n is an integer from to 4, inclusive; R is selected from the group consisting of hydrogen and lower-alkyl of from 1 to 4 carbon atoms, inclusive; and R is selected from the group consisting of hydrogen, lower-alkyl, and loweralkanoyl of from 2 to 4 carbon atoms, inclusive.

In accordance with this invention, the term loweralkyl of from 1 to 4 carbon atoms, inclusive includes methyl, ethyl, pnc pyl, butyl, and isomeric forms thereof. Similarly, the term lower-alhoxy of from 1 to 4 carbon atoms, inclusive, includes methoxy, ethoxy, propoxy, butoxy, and isomeric forms thereof. Halogen includes chlorine, bromine, iodine, and fluorine. The term loweralkanoyl of from 2 to 4 carbon atoms, inclusive, includes acetyl, propionyl, butyryl, and isobutyryl.

The novel compounds of this invention (compounds of Formula 1, above) are useful as intermediates. illustratively, the compounds of Formula I wherein R is hydrogen can be reacted with chlorine to produce activeohlorine compounds in which the N-attached hydrogen atom at position 5 is replaced by a chlorine atom. Furthermore, compounds of Formula I can be cat-alytically hydrogenated in the presence of a hydrogenation catalyst, e.g., platinum or palladium, to obtain the corresponding 3,4 disubstituted-l,2,5-thiadiazolidine-1,1-dioxidcs of the formula:

pounds o-f Formula II are then reacted with chlorine to produce active-chlorine compounds in which one or two N-attached hydrogen atoms are replaced by chlorine. The degree of chlorination (whether one or two atoms of chlorine) depends u'-on the identity of R (wheher hydrogen, lower-alkyl, or lower-alkanoyl) as well as whether chlorination is eilected with one molecular equivalent of chlorine or with two molecular equivalents. The aforesaid active-chlorine compounds are useful as disinfectants, bleaching agents, and zmtiseptics. Moreover, the novel compounds of Formula I wherein R is hydrogen are local anti-inflammatory agents and can be used for treat- Patented Dec. 24, 1%63 2 ing cuts, burns, abrasions, and contusions in mammals, birds, and other animals.

The novel compounds of Formula I wherein R is hydrogen and loWer-alkyl are prepared by condensing a sulfamide of the formula 0 o NH2SNHR wherein R is selected from the group consisting of hydrogen and lower-alkyl, with a benzoin of the formula:

wherein R, X, and n are a defined above. The reactants are mixed in the presence of an inert organic solvent and acid catalyst. Suitable inert organic solvents include methanol, ethanol, isopropyl alcohol, ethanol and water, dioxzme, dimethylformamide, dioxane and water, dimethylformarnide and water, and the like. Suitable acid catalysts include, for example, hydrogen chloride, sulfuric acid, p-toluene-sulfon-ic acid, hydrogen bromide, and the like. The reaction proceeds satisfactorily at temperatures ranging from about 20 C. up to about C., and, advantageously, the reaction mixture is heated at a temperature in the range of about 60 C. up to about 100 C. in order to assure completion of the reaction in a convenient interval of time. The 3,4-disubstituted-A -1,2,5- thiadiazoline-l,l-dioxide thus produced is separated from the reaction mixture and recovered in pure form by conentional procedures such as filtration, solvent evaporation, solvent extraction, and crystallization.

Alternatively, the novel compounds of Formula I wherein R is lower-alkyl can be conveniently prepared by condensing sulfamide with a benzoin of Formula ill and reacting the thus-produced 3,4-disubstituted-A 1,2,5- thiazdiazoline-1,1-dicside (compound according to Formula I wherein R is hydrogen) with a diazoalkane, e.g., diazomethane, diazoethane, diazopiropane, and diazobutane, to produce the corresponding 5-alkyl-3,4-disubstitilted-A 4,2,5-thiadiazoiine-l,l-dioxide. The reaction of a 3,4-disubstituted-u -1,2,5-thiadiazoline-l,l-dioxide with a diazoalkane (preferably an ethereal solution thereof) is conveniently effected at temperatures ranging between about 10 C. and about 30 C. in the presence of an inert solvent such as methylene chloride, chloroform, carbon tetrachloride, and the like.

T e novel compounds of Formula l wherein R is lowerallianoyl are conveniently prepared by condensing sulfamide with a benzoin Formula ill and reacting the thus-produced 3,4-disubstituted-A 1,2,5-tniadiazoline-1,l.- dioxide (compound according to Formula I wherein R is hydrogen) with a loWer-alkanoyl halide, preferably a lower-alkano-yl chloride, e.g., acetyl chloride, prcpionyl chloride, hu-tyryl chloride, and the like.

The benzoin starting compounds having the Formula ill are generally known in the art and can be prepared by known methods. Illustrative known benzoins include benzoin,

a-butylbenzoin,

5 ,5 '-dibromo-2,2-dimethoxybenzoin,

3 3 -.iibronio-2,2,4,4,6,6'-hexamethylbenzoin, 4,4-dibromo-2,2,6,6-tetramethylbenzoin, 2,2'-diethoxybenzoin, 2,2-dimethoxybenzoin, 4,4-dimethcxybenzoin, tit-ethyl-4,4-dimethoxybenzoin, 4,4'-diisopropylbenzoin,

p-toluoin (4,4-dimcthylbenzoin) 2,4,4-trimethylbenzoin,

3 u-ethylbenzoin, 2,2,4,4,6,6-hexaethylbenzoin, 2,2',4,4',6,6'-hexaisopropylbenzoin, 2,2',4,4',6,6-hexamethoxybenzoin, 3,3,4,4,5 ,5 -hexamethoxybenzoin, 2,2,4,4',6,6-hexamethylbenzoin, 4-methoxybenzoin, 4-methoxybenzoin, a-methylbenzoin, 2,2,3,3',5,5,6,6'-octamethylbenzoin, 2,2,4,4,6-pentamethylbenzoin, 2,2,5 ,5 -tetramethoxybenzoin, 2,2,6,6-tetramethylbenzoin,

2, 3,4,6-tetramethylbenzoin, 2,4,4,S-tetramethylbenzoin, 2,4,6-triisopropylbenzoin, 2,4,6-trimethy1benzoin, 2',4',6'-trimethylbenzoin, 4-ch1orobenzoin, 4-chlorobenzoin, 4-chloro-4-methoxybenzoin, ot-tert-butylbenzoin, '2,2-dichlorobenzoin, 4,4'-dichlorobenzoin, 2,4-dimethoxybenzoin, 4-ethoxy-Z-methoxybenzoin, 2-methoxy-2-methylbenzoin, 4'-methylbenzoin,

2,3 ,4,4',6-pentamethoxybenzoin, 3 ,3 ,4,4'-tetramethoxybenzoin, 2,3,4,4-tetramethoxybenzoin, 2,4,4,6'-tetramethoxybenzoin, 2,4,4'-trirnethoxybenzoin, 2,4,6-trimethoxybenzoin, 2,2-dimethoxy-4,4-dichlorobenzoin, 4-butoxybenzoin,

4-ethylbenzoin, 4-methylbenzoin, 4,4-dibromobenzoin, 3-bromobenzoin, 2'-chloro-3,4-diethoxybenzoin, 2-e thoxybenzoin, 2-ethoxybenzoin, 3-chloro-4-methoxybenzoin, and 2,2-dichloro-3,3 '-dimethoxybenzoin.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

Example I.Preparatin of 3,4-Diplzenyl-A -1,2,5 T hiadiazoline-l ,I -Di0xide A mixture consisting of 127.2 g. (0.6 mole) of benzoin and 57.6 g. (0.6 mole) of sulfamide in 600 ml. of absolute ethanol was treated with anhydrous hydrogen chloride gas with rapid stirring until the temperature of the mixture reached 50 C. The reaction mixture was then heated at the reflux temperature for 4 hrs. and concentrated under reduced pressure. The residue was mixed with water and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate and the ether was evaporated. The residue was recrystallized from a mixture of 1 part ethanol and 1 part cyclohexane to give 103 g. (63% yield) of 3,4-di- ;phenyl-A -1,2,5 thiadiazoline 1,1 dioxide as colorless needles melting at 132 to 135 C. A second recrystallization from the same solvent mixture raised the melt- .ingpointto 136 to 137 C.

This compound, when tested in rats, was found to have anti-inflammatory activity.

Analysis.Calcd. for C H N G S: N, Found: N, 10.05; S, 11.44.

Example 2.Preparati0n of 3,4-Di-(p-T0lyl)-A 1,2,5-Thiadiaz0line-1,I-Dioxide FQilQ lS h P CSGUW of Example 1, but substitut- Example 3 .Preparation :0 5 -A cetyl-3,4-Diphenyl-A 1,2,5-Thindiaz0line-1,I-Dioxicle A mixture consisting of 5.45 g. (0.02 mole) of 3,4- diphenyl-A -l,2,5-thiadiazoline-l,1-dioxide (Example 1, above) and 15 ml. of acetyl chloride was heated at the reflux temperature for 1 hr. The excess acetyl chloride was then removed by distillation under reduced pressure. The crude 5-acetyl-3,4diphenylA -1,2,5-thiadiazoline-1,1-dioxide thus obtained was triturated with ethanol, recovered on a filter, and recrystallized from ethyl acetate to give 5.76 g. (92% yield) of 5-acetyl-3,4-diphenyl- A -1,2,5-thiadiazoline 1,1 dioxide as colorless crystals melting at 170 to 171 C.

Analysis.-Calcd. for C H N O S: C, 61.13; H, 4.49; N, 8.91; S, 10.20. Found: C, 61.35; H, 4.62; N, 8.78; S, 10.03.

Following the same procedure, but substituting propionyl chloride, butyryl chloride, and isobutyryl chloride for acetyl chloride, there were prepared 5-propionyl-3,4- diphenyl-A -1,2,5-thiadiaZoline-1, l-dioxide, S butyryl-Zv ,4- diphenyl-A 1,'2,5-thiadiazolirre-1,l-dioxide, and 5 -iso'butyryl-3,4-diphenyl-A 4,2,5-thiadiazoline-1,1 dioxide, respectively.

Example 4 .Preparation of 5 -Methyl-3 ,4-Di many-A 1,2,5-Thiadiaz0line-1,I-Dioxide A solution of 3.20 g. (0.0117 mole) of 3,4-diphenyl- A -1,2,5-thiadiazoline-1,l-dioxide (Example 1, above) in 50 ml. of methylene chloride was mixed with an ethereal solution of diazomethane. After the reaction mixture had been held at about 25 C. for 1 hr., the excess diazomethane was destroyed by addition of acetic acid and the solvent was evaporated. The residue was recrystallized from ethanol. There was thus obtained 1.41 g. of 5 methyl-3,4-diphenyl-A -1,2,5-thiadiazoline-1,1 dioxide as yellow prisms melting at 158 to 160 C.

Analysis.-Calcd. for C H N O S: C, 62.92; H, 4.93; N, 9.79; S, 11.20. Found: C, 62.87; H, 4.87; N, 9.54; S, 11.06.

Following the same procedure, but substituting diazoethane, diazopropane, and diazobutane for diazornethane, there were prepared 5-ethyl-3,4-diphenyl'A -1,2,5-thiadiazoline-1,1-dioxide, 5-propyl-3,4-diphenyl-A 1,2,5 thiadiazoline-Ll-dioxide, and 5-butyl-3,4diphenyl-A -1,2,5- thiadiazoline-l,1-dioxide, respectively.

Example 5 .Preparation of 5-Butyl3,4-Diphenyl-A 1,2,5-Tlriadiaz0line-l,I-Dioxide A mixture consisting of 5.53 g. (0.03 63 mole) of butylsulfamide and 7.70 g. (0.0363 mole) of benzoin in 40 ml. of anhydrous ethanol was treated with hydrogen chloride gas until the temperature of the reaction mixture had increased to about 50 to 60 C. After heating at the reflux temperature for 2%. hrs., the ethanol was evaporated on a steam bath under reduced pressure. The residue thus obtained was diluted with water and the aqueous mixture was extracted several times with ether. The ether extracts were combined, dried over anhydrous magnesium sulfate, and the ether was evaporated. After reorystallizing the residue from ethanol, there wasobtained 4.43 g. of 5-buiyl-3,4-diphenyl-A -1,2,5-thiadiazoline-1,1-dioxide as long colorless prisms melting at 132.5 to 134 C.

Analysis.Calcd. for C H N O Q: C, 65.84; H, 6.14;

' N, 8.53; S, 9.75. Found: C, 65.78; H, 6.15; N, 8.22; S, 9.77.

Following the same procedure but substituting methylsulfamide, ethylsulfamide, and propylsulfarnide for butylsulfarnide, there were obtained 5-methyl-3 ,4-diphen yl-A 1 ,2,5 -thi-adianoline- 1, 1 -dioxide, 5 ethyl-3 ,4-diphenyl-A -1,2,5-thiadiaZoline-1,1-dioxide,

and 5-propyl3,4-diphenyl-A -1,2,5-thiadiazoline-1,1-dioxide, respectively.

Example 6 Following the procedure of Example 1, but substituting 5 ,5 di=brorno-2,2-dimethoxybenzoin, 2,2'-diethoxybenzoin, 4,4'-dimethoxybenzoin, 4,4-diisopropylbenzoin, a,4,4-trimethylbenzoin, a-methylbenzoin, 2,2,4,4',6,6-hexamethoxybenzoin, 4-methoxybenzoin, 2,2',3,3',5,5',6-,6'-octamethylbenzoin, 2,4,6-tr-irnethylbenzoin,

2,4', 6-trimethylbenzoin, a-tert-butylbenzoin, 4-butoxybenzoin, 2,2-dichlorobenzoin, 4-ethoxy-Z-methoxybenzoin, 2-methoxy-2-rnethylbenzo=in, 3-brornobenzoin, and

2-chloro-3,4-diethoxybenzoin for benzoin, there were prepared 3,4-di- (5 -bromo-2-methoxypl1enyl) -A 1,2,5 -thiadiazoline- 1 l-dioxide, 3 ,4-di-( Z-ethoxyphenyl) 3 ,4-di- (4-methoxypheny1) 3 ,4-di- (4-isopropylpheny1) 4-methyl-3,4-di-( 4-methylpheny1) 4-methyl-3,4-diphenyl-, 3 ,4-di- (2,4,6-trimethoxyphenyl) 4-phenyl-3 (4-methoxyphenyl) 3 ,4-di- (2, 3,5 ,6-tetranrethylphenyl) 4-pheny1-3 2,4,6-trimethylphenyl) 4- 2,4,6-trimethylphenyl) -3 -phenyl-, 4-tert-buty1-3,4-diphenyl-, 4-phenyl-3-'( 4-butoxyphenyl) 3 ,4-di- 2-chlorophenyl 4-phenyl-3-(4-ethoxy-2-methoxyphenyl) 4- (Z-methylphenyl) -3 (2-methoxyphenyl) 4-phenyl-3- 3-bromophenyl) and 4 (2-chlorophenyl) -3-( 3,4-diethoxyphenyl) -A -1,2,5-

thiadiazoline-l,l-dioxides, respectively.

Example 7 5 -chloro-3,4-dipheny1-A -1 ,2,5-.thiadiazoli-ne- 1 l-dioxide can be prepared according to the following procedure:

A solution of 27.2 g. (0.1 mole) of 3,4-diphenyl-A 1,2,5-thiadliaZ0line1,l-dioxide (Example 1, above) in. 300 ml. of dry chloroform is treated with chlorine gas at a temperature of about 0 C. to 5 C. until the theoretical amount (7.1 g.; 0.1 mole) has been absorbed. The solvent is then removed at about 25 C. under reduced pressure, to obtain 5-chloro-3,4-diphenyl-A -1,2,5- thiadiazoline-Ll-dioxide as a residue.

1 claim:

1. 3,4-disubstituted-A -1,2,5-thiadiazoline-1,l-dioxide of the formula wherein R is selected from the group consisting of hydrogen and lower-alkyl; R is selected from the group consisting of hydrogen, lower-alkyl, and lower-alkanoyl; X is selected from the group consisting of lower-alkyl, loweralkoxy, and halogen; and n is an integer from 0 to 4, inelusive.

2. 3,4-dipher1yl-A -1 ,2,5-thiadiaZoline-1, l-dioxide.

3. 3,4 di (lower alkylphenyl) A 1,2,5 thi-adiazoline-1,1-dioxide.

4. 3,4-di-(p-tolyl)-A -1,2,5-thiadiazoline-1,l-dioxide.

5. 5 lower 'alkyl 3,4 diphenyl A 1,2,5 thiadiazoline-1,1-dioxide.

6. 5 methyl 3,4 diphenyl A 1,2,5 thiadiazoline- 1,1-dioxide.

7. 5 butyl 3,4 diphenyl A 1,2,5 thiadiazoline- 1,1-dioxide.

8. 5 acetyl 3,4-diphenyl A 1,2,5 thiadiazoline- 1, 1 dioxide.

9. The process which comprises reacting a compound having the formula NH S-NHR" wherein R" is selected from the group consisting of hydrogen and lower-alkyl with a benzoin of the formula H O 0 II 1 XX, R Xn wherein R is selected from the group consisting of hydrogen and lower-alkyl; X is selected from the group consisting of lower-alkyl, lower-alkoxy, and halogen; and n is an integer from 0 to 4, inclusive, to produce a 3,4-disubstituted-A -1,2,5-thiadiazoline-1,l-dioxide of the formula wherein R, R", X, and n are as defined above.

No references cited. 

1. 3,4-DISUBSTITUTED $2-1,2,5-THIADIAZOLIEN-1,1-DIOXIDE OF THE FORMULA
 9. THE PROCESS WHICH COMRPISES REACTING A COMPOUND HAVING THE FORMULA 